Analysis of radioprotection and antimutagenic effects of Ilex paraguariensis infusion and its component rutin

DNA repair pathways, cell cycle checkpoints, and redox protection systems are essential factors for securing genomic stability. The aim of the present study was to analyze the effect of Ilex paraguariensis (Ip) infusion and one of its polyphenolic components rutin on cellular and molecular damage induced by ionizing radiation. Ip is a beverage drank by most inhabitants of Argentina, Paraguay, Southern Brazil, and Uruguay. The yeast Saccharomyces cerevisiae (SC7Klys 2-3) was used as the eukaryotic model. Exponentially growing cells were exposed to gamma rays (γ) in the presence or absence of Ip or rutin. The concentrations used simulated those found in the habitual infusion. Surviving fractions, mutation frequency, and DNA double-strand breaks (DSB) were determined after treatments. A significant increase in surviving fractions after gamma irradiation was observed following combined exposure to γ+R, or γ+Ip. Upon these concomitant treatments, mutation and DSB frequency decreased significantly. In the mutant strain deficient in MEC1, a significant increase in γ sensitivity and a low effect of rutin on γ-induced chromosomal fragmentation was observed. Results were interpreted in the framework of a model of interaction between radiation-induced free radicals, DNA repair pathways, and checkpoint controls, where the DNA damage that induced activation of MEC1 nodal point of the network could be modulated by Ip components including rutin. Furthermore, ionizing radiation-induced redox cascades can be interrupted by rutin potential and other protectors contained in Ip.

Quercetin and rutin as potential agents antifungal against Cryptococcus spp / Quercetina e rutina: potenciais agentes para terapia antifúngica

Abstract Amphotericin B is a fungicidal substance that is treatment of choice for most systemic fungal infections affecting as cryptococcosis the immunocompromised patients. However, severe side effects have limited the utility of this drug. The aim of this study was to evaluate the antifungal effect of the combination of amphotericin B with quercetin or rutin and as a protective of citotoxic effect. The antifungal activity to amphotericin B, quercetin and rutin alone and in combination was determined in Candida sp and Cryptococcus neoformans strains. Cytotoxicity test on erythrocytes was performed by spectrophotometric absorbance of hemoglobin. The amphotericin B MIC was reduced when used in combination with quercetin or rutin to C. neoformans ATCC strain and reduced when combined with rutin to a clinical isolate of C. neoformans. In addition, the combination of quercetin with amphotericin B may reduce the toxicity of amphotericin B to red blood cells. Our results suggest that quercetin and rutin are potential agents to combine with amphotericin B in order to reduce the amphotericin dose to lessen side effects and improve antifungal efficacy.

Resumo A anfotericina B é uma substância fungicida e é o tratamento de escolha para a maioria das infecções fúngicas sistêmicas que afetam os pacientes imunocomprometidos, como a criptococose. No entanto, as severas reações adversas têm limitado a utilização desta droga. O objetivo deste estudo foi avaliar o efeito antifúngico e o potencial efeito protetor de citotoxicidade da combinação de anfotericina B com quercetina ou rutina. A atividade antifúngica de anfotericina B, quercetina e rutina, isoladamente e em combinação foi determinada em cepas de Candida sp e Cryptococcus neoformans. O teste de citotoxicidade em eritrócitos foi realizado por espectrofotometria, através da determinação da absorbância da hemoglobina. A concentração inibitória mínima da anfotericina B foi reduzida quando utilizada em combinação com a quercetina e rutina em C. neoformans ATCC e reduzida quando combinados com rutina em um isolado clínico de C. neoformans. Além disso, a combinação de quercetina com anfotericina B pode reduzir a toxicidade da droga em eritrócitos. Os resultados sugerem que quercetina e rutina são potenciais agentes para combinação com anfotericina B, a fim de reduzir a dose de anfotericina, diminuindo os efeitos colaterais e melhorando sua eficácia antifúngica.

Anti-Proliferative Effects of Rutin on OLETF Rat Vascular Smooth Muscle Cells Stimulated by Glucose Variability

PURPOSE: Proliferation of vascular smooth muscle cells (VSMCs) plays a crucial role in atherosclerosis. Rutin is a major representative of the flavonol subclass of flavonoids and has various pharmacological activities. Currently, data are lacking regarding its effects on VSMC proliferation induced by intermittent hyperglycemia. Here, we demonstrate the effects of rutin on VSMC proliferation and migration according to fluctuating glucose levels. MATERIALS AND METHODS: Primary cultures of male Otsuka Long-Evans Tokushima Fatty (OLETF) rat VSMCs were obtained from enzymatically dissociated rat thoracic aortas. VSMCs were incubated for 72 h with alternating normal (5.5 mmol/L) and high (25.0 mmol/L) glucose media every 12 h. Proliferation and migration of VSMCs, the proliferative molecular pathway [including p44/42 mitogen-activated protein kinases (MAPK), mitogen-activated protein kinase kinase 1/2 (MEK1/2), p38 MAPK, phosphoinositide 3-kinase (PI3K), c-Jun N-terminal protein kinase (JNK), nuclear factor kappa B (NF-kappaB), and Akt], the migratory pathway (big MAPK 1, BMK1), reactive oxygen species (ROS), and apoptotic pathway were analyzed. RESULTS: We found enhanced proliferation and migration of VSMCs when cells were incubated in intermittent high glucose conditions, compared to normal glucose. These effects were lowered upon rutin treatment. Intermittent treatment with high glucose for 72 h increased the expression of phospho-p44/42 MAPK (extracellular signal regulated kinase 1/2, ERK1/2), phospho-MEK1/2, phospho-PI3K, phospho-NF-kappaB, phospho-BMK1, and ROS, compared to treatment with normal glucose. These effects were suppressed by rutin. Phospho-p38 MAPK, phospho-Akt, JNK, and apoptotic pathways [B-cell lymphoma (Bcl)-xL, Bcl-2, phospho-Bad, and caspase-3] were not affected by fluctuations in glucose levels. CONCLUSION: Fluctuating glucose levels increased proliferation and migration of OLETF rat VSMCs via MAPK (ERK1/2), BMK1, PI3K, and NF-kappaB pathways. These effects were inhibited by the antioxidant rutin.

Rutin ameliorates methotrexate induced hepatic injury in rats

PURPOSE: To investigate the possible protective effect of rutin on methotrexate induced hepatotoxicity in rats. METHODS: Twenty-two rats were divided into three experimental groups; Control-saline, Mtx, Mtx+Rutin. Hepatic tissue was taken for histological assessment and biochemical assays. Oxidative stress parameters malondialdehyde (MDA), glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) were investigated. Liver markers aspartate aminotransferase (AST), alanine aminotransferase (ALT) were analyzed in serum. RESULTS: Mtx+Rutin group showed lower histological injury compared to Mtx group, MDA and ALT levels were increased, while SOD and GSH-Px were decreased in Mtx group compared with Control-saline group. MDA and ALT levels were increased, while SOD and GSH-Px were decreased in Mtx group, compared with Mtx +Rutin group. Serum AST levels were similar among the groups. CONCLUSION: Rutin may be a potential adjuvant drug to reduce the hepatic side effects observed during Mtx therapy for various clinical conditions.

Hepato-protective effect of rutin via IL-6/STAT3 pathway in CCl4-induced hepatotoxicity in rats

BACKGROUND: Carbon tetrachloride (CCl4) induces hepatotoxicity in animal models, including the increased blood flow and cytokine accumulation that are characteristic of tissue inflammation. The present study investigates the hepato-protective effect of rutin on CCl4-induced hepatotoxicity in rats. RESULTS: Forty male Wistar rats were divided into four groups. Group I (control group) received 1 mL/kg of dimethyl sulfoxide intragastrically and 3 mL/kg olive oil intraperitoneally twice a week for 4 weeks. Group II received 70 mg/ kg rutin intragastrically. Groups III and IV received CCl4 (3 mL/kg, 30 % in olive oil) intraperitoneally twice a week for 4 weeks. Group IV received 70 mg/kg rutin intragastrically after 48 h of CCl4 treatment. Liver enzyme levels were determined in all studied groups. Expression of the following genes were monitored with real-time PCR: interleukin-6 (IL-6), dual-specificity protein kinase 5 (MEK5), Fas-associated death domain protein (FADD), epidermal growth factor (EGF), signal transducer and activator of transcription 3 (STAT3), Janus kinase (JAK), B-cell lymphoma 2 (Bcl2) and B-cell lymphoma-extra-large (Bcl-XL). The CCl4 groups showed significant increases in biochemical markers of hepatotoxicity and up-regulation of expression levels of IL-6, Bcl-XL, MEK5, FADD, EGF, STAT3 and JAK compared with the control group. However, CCl4 administration resulted in significant down-regulation of Bcl2 expression compared with the control group. Interestingly, rutin supplementation completely reversed the biochemical markers of hepatotoxicity and the gene expression alterations induced by CCl4. CONCLUSION: CCl4 administration causes alteration in expression of IL-6/STAT3 pathway genes, resulting in hepatotoxicity. Rutin protects against CCl4-induced hepatotoxicity by reversing these expression changes.

Anti-hyperglycemic activity of Rutin in streptozotocin-induced diabetic rats: An effect mediated through cytokines, antioxidants and lipid biomarkers.

Administration of rutin (50 and 100 mg/kg) and pioglitazone (10 mg/kg) orally for 3 weeks treatment significantly improved body weight, reduced plasma glucose and glycosylated hemoglobin, pro-inflammatory cytokines (IL-6 and TNF-α), restored the depleted liver antioxidant status and serum lipid profile in high fat diet + streptozotocin induced type 2 diabetic rats. Rutin treatment also improved histo-architecture of ß islets and reversed hypertrophy of hepatocytes. Rutin exhibited significant antidiabetic activity, presumably by inhibiting inflammatory cytokines, improving antioxidant and plasma lipid profiles in High fat diet + streptozotocin induced type 2 diabetic model and may be useful as a diabetic modulator along with standard antidiabetic drugs. However, such effects need to be confirmed on human subjects in clinical condition.

Rutin ameliorates glycemic index, lipid profile and enzymatic activities in serum, heart and liver tissues of rats fed with a combination of hypercaloric diet and chronic ethanol consumption.

Alcoholism and obesity are strongly associated with several disorders including heart and liver diseases. This study evaluated the effects of rutin treatment in serum, heart and liver tissues of rats subjected to a combination of hypercaloric diet (HD) and chronic ethanol consumption. Rats were divided into three groups: Control: rats fed a standard diet and drinking water ad libitum; G1: rats fed the HD and receiving a solution of 10% (v/v) ethanol; and G2: rats fed the HD and ethanol solution, followed by injections of 50 mg/kg-1 rutin as treatment. After 53 days of HD and ethanol exposure, the rutin was administered every three days for nine days. At the end of the experimental period (95 days), biochemical analyses were carried out on sera, cardiac and hepatic tissues. Body weight gain and food consumption were reduced in both the G1 and G2 groups compared to control animals. Rutin effectively reduced the total lipids (TL), triglycerides (TG), total cholesterol (TC), VLDL, LDL-cholesterol and glucose levels, while it increased the HDL-cholesterol in the serum of G2 rats, compared to G1. Although rutin had no effect on total protein, albumin, uric acid and cretinine levels, it was able to restore serum activities of alkaline phosphatase (ALP), lactate dehydrogenase (LDH), aspartate aminotransferase (AST), alanine aminotransferase (ALT) and creatine kinase (CK) in animals fed HD and receiving ethanol. Glycogen stores were replenished in both hepatic and cardiac tissues after rutin treatment. Moreover, rutin consistently reduced hepatic levels of TG and TC and cardiac AST, ALT and CK activities. Thus, rutin treatment was effective in reducing the risk factors for cardiac and hepatic disease caused by both HD and chronic ethanol consumption.

Maqui (Aristotelia chilensis) and rutin (quercetin-3-O-rutinoside) protects against the functional impairment of the endothelium-dependent vasorelaxation caused by a reduction of nitric oxide availability in diabetes / El Maqui (Aristotelia chilensis) y la rutina (quercetin-3-O-rutinoside) protegen contra el deterioro funcional de la vasorelajación dependiente de endotelio causada por la reducción de la disponibilidad de óxido nítrico en diabetes

The present study evaluated the beneficial effect of hydroalcoholic extract of maqui berry (Aristotelia chilensis, Elaeocarpaceae) and rutin (quercetin-3-o-rutinoside) against vascular reactivity impairment, hyperglycemia and dyslipidemia of alloxan (alx) diabetic rats. The chronic maqui berry extract (mbe) treatment significantly corrected all the above abnormalities in diabetic rats. Rutin reduced fasting blood sugar and improved the impaired endothelium-dependent relaxations. Maqui reduced plasma levels of cholesterol, LDL and triglycerides and increased body weight of diabetic rats. Removal of the endothelium and nitric oxide synthase (NOS) inhibitor, NG-Nitro-L-Arginine Methyl Ester (L-NAME) increased the phenylephrine response, and sensitivity to sodium nitroprusside (SNP) did not differ between tested groups. Maqui and rutin improved nitric oxide bioavailability, and these findings indicate that Aristotelia chilensis could be a candidate of natural medicine for diabetes.

El presente estudio evaluó el efecto beneficioso del extracto hidroalcohólico de maqui (Aristotelia chilensis, Elaeocarpaceae) y rutina (quercetina-3-o-rutinósido) contra el deterioro de la reactividad vascular, hiperglucemia y dislipidemia de ratas diabéticas. El tratamiento crónico con el extracto corrigió en gran medida esas alteraciones. Rutina redujo el azúcar en sangre y mejoró la relajación dependiente de endotelio. Maqui redujo los niveles plasmáticos de colesterol, LDL y triglicéridos y aumentó del peso de las ratas diabéticas. La eliminación del endotelio y el inhibidor de la sintasa de óxido nítrico, NG-Nitro-L-Arginina Metil Éster (L-NAME) aumentaron la respuesta a la fenilefrina y, la sensibilidad al nitroprusiato de sodio, no cambió entre los diferentes grupos. Maqui y rutina mejoraron la biodisponibilidad del óxido nítrico. Estos hallazgos indican que Aristotelia chilensis podría ser un candidato de la medicina natural para la diabetes.

Effect of bioactive compounds extracted from euphorbious plants on hematological and biochemical parameters of Channa punctatus / Efeito de compostos bioativos extraídos de plantas eufórbicas sobre os parâmetros hematológicos e bioquímicos da Channa punctatus

Channa punctatus was exposed to four different concentrations of Rutin, Taraxerol and Apigenin. Changes in some hematological parameters of Channa punctatus were assessed to determine the influence of these compounds on test fish. Fish were exposed to sublethal concentrations (80 percent of LC50 of 24h) of these compounds for one week. Control fish were also administered for one week. Thereafter, blood samples were obtained from the control and experimental fish. Blood was assayed for selected hematological parameters (hematocrit, hemoglobin, red blood cell count, white blood cell count total plasma protein and plasma glucose concentration). The derived hematological indices of mean corpuscular hemoglobin concentration (MCHC), mean corpuscular hemoglobin (MCH) and mean corpuscular volume (MCV) were calculated. Sublethal concentrations of these compounds caused a dose dependent decrease in hemoglobin values coupled with a decrease in hematocrit values and red blood cell counts are an obvious indication of anemia. The total white blood cell counts and the differential white blood cell counts were decreased except for the lymphocytes, where there was a slight increase. Plasma protein and glucose were also lower in exposed fish when compared with control. The hematological indices MCH, MCHC, MCV were also lowered. The result from this study reveals high mortality rate and deleterious consequences on the health of fish subjected to acute exposure of Rutin, Taraxerol and Apigenin and therefore, should not be used directly in aquaculture without having the proper knowledge.

Channa punctatus foi exposta a quatro diferentes concentrações de Rutina, Taraxerol e Apigenina. Alterações de alguns parâmetros hematológicos da Channa punctatus foram acessados para determinar a influência destes compostos no peixe teste. Peixes foram expostos a concentrações sub-letais (80 por cento 0f LC50 em 24h) destes compostos por uma semana. Os peixes controles foram também expostos durante uma semana. A seguir, amostras de sangue foram obtidas do peixe controle e do experimental. O sangue foi estudado por parâmetros hematológicos selecionados (hematócrito, hemoglobina, contagem de células vermelhas e brancas, proteína plasmática total e concentração de glucose plasmática). Os índices hematológicos derivados da média da concentração corpuscular da hemoglobina (MCHC), a média de hemoglobina corpuscular (MCH) e a média de volume corpuscular (MCV), foram calculados. Concentrações sub-letais destes compostos causaram decréscimo dose-dependente dos valores da hemoglobina unidos a decréscimo de valores de hematócrito e das contagens de células sanguíneas vermelhas o que caracteriza indicação óbvia de anemia. As contagens totais de células brancas e a contagem diferencial destas células estavam diminuídas exceto pelos linfócitos que mostraram leve aumento. A proteína plasmática e a glicose estavam também baixas nos peixes expostos quando comparados com o controle. Os índices hematológicos MCH, MCHC, MCV estavam também diminuídos. Os resultados deste estudo revelam alto percentual de mortalidade e conseqüências deletérias à saúde de peixes submetidos à exposição aguda de Rutina, Talaxerol e Apigenina e portanto eles não devem ser usados diretamente em aquacultura sem conhecimento apropriado.

Modulatory effects of rutin on biochemical and hematological parameters in hypercholesterolemic Golden Syrian hamsters

Flavonoids have been reported to exhibit several pharmacological properties, mainly in cardiovascular and inflammatory diseases. In the present study, we observed that rutin, a known glycosylated flavonoid isolated from Dimorphandra mollis, had a lowering effect on plasma triglyceride levels of diet-induced hypercholesterolemic Golden Syrian hamsters, but did not change total cholesterol and high-density lipoprotein cholesterol levels. Moreover, high-fat or rutin supplemented diets showed no immunotoxic effects, since no significant changes were observed on total white blood cells, granulocytes and mononuclear cells, as well as on the neutrophil apoptosis degree, when compared to untreated animals. Therefore, rutin seems to be a selective and non-toxic modulator of hypercholesterolemia, which can be promising for the development of new drugs.

Os flavonóides possuem diversas propriedades farmacológicas, principalmente nas doenças cardiovasculares e inflamatórias. No presente estudo, observamos que a rutina, um conhecido flavonóide glicosilado isolado da Dimorphandra mollis, diminuiu o nível de triglicerídeos plasmáticos em hamsters Golden Syrian hipercolesterolêmicos sem alterar os níveis de colesterol total e colesterol HDL. Além disso, observamos que dietas hipercolesterolêmicas ou suplementadas com rutina não apresentaram efeito imunotóxico, uma vez que nenhuma alteração significativa foi observada nos leucócitos totais, granulócitos e células mononucleares, bem como no grau de neutrófilos em apoptose, quando comparado com animais não tratados. Portanto, a rutina parece ser um modulador seletivo e não tóxico da hipercolesterolemia, o que pode ser promissor para o desenvolvimento de novos fármacos.

Rutina: estrutura, metabolismo e potencial farmacológico / Rutin: estructure, metabolism and pharmacological potency

Os Flavonóides são substâncias naturais amplamente distribuídas no Reino Vegetal. Há um interesse crescente na investigação dessas substâncias, devido ao volume de evidência dos benefícios que eles proporcionam para a saúde. A Rutina é um flavonol glicosídico pertencente a uma importante classe de Flavonóides, sendo extensamente encontrados na natureza, em frutas, vegetais e bebidas como chá e vinho. Pouco se sabe sobre a farmacocinética e biodisponibilidade da rutina, e estes mecanismos tem sido foco de muita controvérsia. Apesar disso, a Rutina apresenta grande importância terapêutica por melhorar a resistência e permeabilidade dos vasos capilares, atividades antioxidante, antiinflamatória, anticarcinogênica dentre outras, razão que levou à realização da presente revisão.

Flavonoids are natural products widely distributed in the vegetable kingdom. There has been increasing interest in research of flavonoids, due to growing evidence of the health benefits of them. Rutin is a glycoside flavonol which belongs to an important class of flavonoids, being extensively found in the nature in fruit, vegetable and beverages, such as tea and wine. About the pharmacokinetics and bioavailability of Rutin, little is stil know, and tis mechanisms have been a matter of much controversy. Dispite it, Rutin presents a therapeutical importance due to improve resistance and permeability of capillaries vessels, antioxidante, antiinflamatory, anticarcinogenic and other important activities. Reason that led to the completion of this review.

Rutin inhibits osteoclast formation by decreasing reactive oxygen species and TNF-alpha by inhibiting activation of NF-kappaB

Rutin, a glycoside of flavonol, inhibits osteoclast formation induced by receptor activator of NF-kappaB ligand (RANKL) in bone marrow-derived macrophages. It reduces reactive oxygen species produced by RANKL and its inhibitory effect results from reduced levels of TNF-alpha Rutin also lowers NF-kappaB activation in response to RANKL.

Synergism of flavonoids with bacteriostatic action against Staphylococcus aureus ATCC 25 923 and Escherichia coli ATCC 25 922

In our previous studies, bacteriostatic action of flavonoids against Staphylococcus aureus ATCC 25 923 and Escherichia coli ATCC 25 922 was demostrated. In the present work synergism of their combinations in order to improve the bacteriostatic action against the same microorganisms was determined. The experiences were made in nutritive broth, maintaining constant one drug concentration (20 µg/ml) and increasing the other one. A turbidimetric kinetic method was used and by means of a mechanism previously proposed, the minimal inhibitory concentrations (MIC's) of each flavonoid combination were determined. The MIC's for assayed combinations against S. aureus were: variable morin - constant rutin: 157.44 µg/ml and variable quercetin - constant morin: 29.9 µg/ml. The values obtained against E. coli were: variable morin - constant rutin: 78.5 µg/ml; variable quercetin -constant rutin: 47.4 µg/ml; variable quercetin - constant morin: 25 µg/ml; variable morin - constant quercetin: 27.4 µg/ml.